PB2314: OLIPUDASE ALFA FOR ADULTS WITH ACID SPHINGOMYELINASE DEFICIENCY: IMPROVEMENTS IN CROSSOVER PLACEBO PATIENTS AND FURTHER IMPROVEMENTS IN ORIGINAL OLIPUDASE ALFA PATIENTS AFTER 2 YEARS IN ASCEND TRIAL
Authors: J. Villarrubia, M. Wasserstein, A. Barbato, R. C. Gallagher, R. Giugliani, N. B. Guelbert, J. B. Hennermann, C. Hollak, T. Ikezoe, R. Lachmann, O. Lidove, P. Mabe, E. Mengel, M. Scarpa, E. Senates, M. Tchan, B. L. Thurberg, A. Yarramaneni, A. M. Rawlings, Y. Kim, M. Kumar
Journal: HemaSphere (2022)

Background: Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal storage disease characterized by pulmonary dysfunction, hepatosplenomegaly, thrombocytopenia/bleeding issues, and dyslipidemia. Disease awareness is low and diagnostic delays are common. Undiagnosed patients may be referred to hematologists for thrombocytopenia/bleeding issues and splenomegaly. Olipudase alfa, intravenous-recombinant-human ASM, is in late-stage development (Sanofi Genzyme) for non-central-nervous-system manifestations of ASMD. The ASCEND study (NCT02004691), a phase 2/3 placebo-controlled trial in 36 adults with ASMD, has completed its primary analysis. At Year 1, olipudase alfa patients compared to placebo patients (1:1 randomization) had statistically significant increases in %predicted diffusing capacity of carbon monoxide (DLCO) and decreases in spleen and liver volume. Thirty-five patients continued in an open-label trial extension: 17/18 placebo patients, 18/18 olipudase alfa patients. Aims: We report Year 2 results for the former placebo patients after 1 year of olipudase alfa (crossover group) and for the continuing olipudase alfa patients after 2 years of olipudase alfa (original olipudase alfa group). Methods: Patients underwent dose-escalation to 3.0 mg/kg every 2 weeks for ~14 weeks when starting olipudase alfa. Changes from baseline are presented as least-square (LS) mean ANCOVA % change ±standard error of the mean for %-predicted DLCO, spleen volume, liver volume, platelet count, liver function, and lipid profile. Change in lung high-resolution computed tomography (HRCT) scores for ground glass appearance is presented as LS mean ANCOVA absolute change from baseline. Results: Thirty-three of 35 patients completed Year 2. In Year 2, improvements for crossover patients paralleled the olipudase alfa group in the primary analysis and improvements continued for the original olipudase alfa group (Table). In the crossover group, spleen volume decreased by 36.0±3.0% (n=11); %-predicted DLCO increased by 28.0±6.2% (n=10); spleen volume decreased by 36.0±3.0% (n=11); liver volume decreased by 30.7±2.5% (n=11), and platelet count increased by 21.7±6.4% (n=15). In the original olipudase alfa group, %-predicted DLCO increased by 22.2±3.4% (n=17) at Year 1 and 28.5±6.2% at Year 2 (n=10); spleen volume decreased by 39.5±2.4% (n=17) at Year 1 and 47.0±2.7% (n=14) at Year 2; liver volume decreased by 27.8±2.5% (n=17) at Year 1 and 33.4±2.2% (n=14) at Year 2, and platelet count increased by 16.6 ±4.0% at Year 1 (n=18) and 24.9±6.9% (n=13) at Year 2. HRCT ground glass appearance score decreased by 0.30±0.5 (n=14) at Year 2 for the crossover group and decreased by 0.45±0.13 (n=18) at Year 1 and 0.48±0.07 (n=16) at Year 2 for the original olipudase alfa group. Improvements in dyslipidemia, liver function, liver sphingomyelin clearance, and plasma lyso-sphingomyelin in crossover patients paralleled those seen in the original olipudase alfa patients in Year 1; original olipudase alfa patients maintained these benefits in Year 2. Overall, 99% of treatment-emergent adverse events (AEs) were mild or moderate, with one treatment-related serious AE. No patient discontinued due to an AE. Image:Summary/Conclusion: Crossover patients had the same magnitude and time course of clinical improvement seen in patients receiving olipudase alfa for 1 year, while 2-year olipudase alfa patients had sustained or further improvements. Olipudase alfa reduces manifestations of chronic ASMD in adults and has sustained efficacy. Increased awareness of ASMD among hematologists is important for timely diagnosis and disease management.